Immunotherapeutic Strategies in RRMM: Differentiating Between Emerging Approaches

Dr. Irene GhobrialIrene Ghobrial, MD
Professor
Dana-Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts

We’ve recently seen a number of breakthroughs regarding the use of immunotherapy in a variety of cancer types, and more recently, some approaches are showing great promise in multiple myeloma. Could you provide some historical perspective on the development of immunotherapeutics in this disease area?

Myeloma is actually one of the first cancers in which immunotherapy was used, if we consider drugs like thalidomide, lenalidomide, and pomalidomide, which have multiple immunomodulatory effects that include alterations in cytokine production, co-stimulation of T cells, and enhancement of NK cells,1 So in fact we have had immunomodulatory drugs (IMiDs) in myeloma,—but not the perfect immunotherapy.

Then along came PD-1/PD-L1 inhibitors and other immune checkpoint inhibitors, which completely changed the way we think about melanoma, lung cancer, and other solid tumors. In myeloma, we saw very promising responses in phase 2 studies of immune checkpoint inhibitors combined with either lenalidomide or pomalidomide and dexamethasone; those led to phase 3 studies that were ultimately disappointing due to toxicity, and the U.S. Food and Drug Administration (FDA) suspended two pembrolizumab phase 3 trials.2

So suddenly we were back to square one, asking whether we should be using immune checkpoint inhibitors. I think we still have to consider that among all these heavily pre-treated, relapsed/refractory patients, there may be subgroups of patients with remarkable responses that we could be targeting with checkpoint inhibitors. Meanwhile, however, the conversation about immunotherapy in myeloma has shifted to include discussion of B-cell maturation antigen (BCMA), whether it is in the context of antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), or chimeric antigen receptor (CAR) T-cell therapy.

Could you describe the rationale for BCMA-directed therapy in myeloma? Why is this a promising therapeutic approach?

For many years, we have been looking for antibodies for myeloma. We know that rituximab, a monoclonal antibody directed against the CD20 B-cell surface antigen, has worked very well for lymphoma. There are several well-recognized surface antigens on myeloma cells, including CD38, SLAMF7, and now BCMA. Of note, CD38 is also expressed on many other cells, including immune cells, so we were surprised that the anti-CD38 monoclonal antibody daratumumab worked as well as it does, with manageable toxicity, despite CD38 expression on non-myeloma cells. The antigen SLAMF7, the target of elotuzumab, is not only highly expressed on myeloma cells, but is also expressed on NK cells, and activation of NK cells via engagement with SLAMF7 is thought to partially explain the mechanism of action of elotuzumab.3 And then there is BCMA, which is expressed on all plasma cells, and we now know that the level of expression is not that important for targeting BCMA. Beyond plasma cells, it is not expressed on too many other cells, which makes it a promising target and may help with avoiding toxicity in patients who receive BCMA-directed therapy.

You mentioned ADCs, BiTEs, and CAR T-cell therapies that utilize BCMA as a target. How do these approaches differ?

These all target BCMA, but they work in very different ways. The BCMA-directed ADC belantamab mafodotin was recently granted priority review for relapsed/refractory myeloma by the FDA.4 This is a toxin being delivered by a monoclonal antibody that goes after anything that expresses BCMA, and it has shown amazing responses in our patients with relapsed/refractory myeloma. The data is very compelling, even in heavily pretreated patients.5 The hope is that there would be more such ADCs, because if you have already used CD-38 antibodies like daratumumab, you would like to see something else to potentially treat your patients afterward.

If by contrast we look at mechanisms of BCMA engagement that involve immune cell regulation, then we have the BiTEs and the CAR T-cell therapies. CAR T-cells have demonstrated remarkable results in CD19-expressing hematologic malignancies. While myeloma cells are generally CD19-negative, there is a small subset of CD19-positive myeloma stem-like cells, and there are a few positive reports including one study in which 2 of 10 patients with refractory myeloma had significantly longer progression-free survival (PFS) after autologous stem cell transplant (ASCT) plus anti-CD19 CAR T-cells.6

There are other approaches to developing CAR T-cells than involve SLAMF7, CD38, CD138, and other targets, though BCMA has been the most successful. This has led to a long list of BCMA CAR Ts, whether as CAR T alone or with different modalities, such as inhibiting the PI3K/Akt pathway during production, to enhance the activity of the T-cells or prevent T-cell exhaustion.7 I would say that CAR T-cell therapy is still in its infancy, and there are second-, third-, and fourth-generations that will come along, as well as using CAR T-cells in combination with other treatments.

In the big picture, bb2121 is one of the most advanced of the anti-BCMA CAR T-cell therapies. This approach has recently demonstrated promising anti-tumor activity in heavily pretreated patients8—many of them had their PET/CT scans lighting up like a Christmas tree, almost on hospice care, and getting a very fast response. Another promising anti-BCMA CAR T-cell therapy is LCAR-B38M, which demonstrated impressive deep and durable responses in a phase 1 trial.9 The median number of prior therapies in this trial was three, which begs the question of whether we would see longer remission with CAR T-cells if we treated our myeloma patients before they are on the 9th or 10th line of therapy. For example, if we think of a 30-year-old patient with myeloma, the question may be, will I give them daratumumab-RVd and transplant, or should I start thinking of what is the next step so that they do not relapse 5 to 6 years from now? This is where we think immunotherapy could have a huge impact in those patients, because if we give it early when their immune response is still working well, when they have minimal disease burden, likely they will have less toxicity and a longer remission.

In general, patients are having impressive responses to the many anti-BCMA CAR T-cell therapies. However, the duration of response is about one year. So are we really curing patients with CAR Ts? The answer is no. Can we improve on it? Absolutely. There are so many ways of thinking about it: Can we overcome T-cell exhaustion?  Can we potentially re-infuse CAR Ts?  Can we give it earlier? Can we add to it?  Can we add an IMiD?  Can we add daratumumab? There are lots a of opportunities to improve. This is one of the first success stories showing that immunotherapy works extremely well in multiple myeloma. We see responses in patients who could not tolerate anything else, and were going to die, so even if they live one year before they relapse, that is an extra one year of survival that they would not have had otherwise. I think the biggest problem right now is how to overcome cytokine release syndrome (CRS), and how to overcome the central nervous system (CNS) issues.

Where do BiTEs fit into this picture?

The CAR T-cell therapies are very promising, but come with certain limitations. They require that you harvest the cells, manipulate them, then give them back to the patient. There is much to be done, making it a complex and expensive procedure. This is where I think bispecifics come in – these are but off-the-shelf, so you do not need to take that patient’s cells and engineer them. You can give it in the community. You can combine it with other agents. Currently, BiTEs are still in their early phase 1 and phase 2 trials, but they are showing much promise because they overcome a lot of those potential limitations of CAR T-cells. They are associated with CRS, but perhaps not as much as with CAR T-cell therapy, and they do have neuropathy and other conventional side effects.

Perhaps the most advanced of the BiTEs is AMG 420. In a phase 1 dose escalation study, AMG 420 given by continuous infusion had a response rate of 70%, or 7 out of 10 patients, including 5 of 7 responders achieving a stringent complete response at the dose recommended for further investigation.10 Subsequently, we have seen early reports for AMG 701, a next-generation BiTE that can be given in weekly short-term infusions.11 We also just saw impressive data from the first clinical study of CC-93269, an anti-BCMA T-cell engager; in a phase 1 multicenter trial including patients with relapsed/refractory multiple myeloma, CC-93269 had a manageable safety profile and promising efficacy, including a 75% rate of minimal residual disease (MRD) negativity.12 It’s a short duration of follow-up, so it is hard to know whether the excitement we have now with bispecifics is the same as when we hoped CAR T-cells were the cure, and then we lost that excitement when we started seeing relapses—or is it truly something that will be maintained for a long time.

What is the outlook for anti-BCMA therapies in 2020 and beyond?

I think the field will explode in the next few years. We are just at the beginning of immunotherapies in myeloma. I think CAR-NK cell therapy will be promising, and we not only have bispecifics, but now we have a trispecific antibody that targets cancer cells, a T-cell activating receptor, and a T-cell protein that promotes enduring T-cell activity.13 The next generations of CAR T-cell therapy could include off-the-shelf approaches or allogeneic CAR T-cells, and we could see a re-exploration of immune checkpoint inhibitors—not only PD-1/PD-L1, but all the other immune checkpoint regulators that are available, to determine which ones may truly work in multiple myeloma.


References

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